BACKGROUND:The evaluation of innovative oncology medicines presents significant challenges related to the selection of appropriate clinical endpoints and the sufficiency of evidence, particularly in therapeutic areas, such as immunotherapies, targeted treatments, single-arm trials, and tumor-agnostic therapies. In these contexts, the added value of new treatments is often not adequately captured by traditional clinical trial endpoints, such as overall survival (OS), which remains the gold standard in oncology assessment. This article aims to analyze the main sources of uncertainty in the value assessment of oncology therapies in Spain, with a focus on the limitations of current endpoints and evidence-generation processes, and to provide recommendations for enhancing the recognition and assessment of additional clinical benefit. METHODS:A multidisciplinary expert panel composed of twelve professionals, including medical oncologists, hospital pharmacists, health economists, and patient representatives, was convened to identify and discuss key sources of uncertainty in the value assessment of oncology treatments, particularly those related to clinical endpoint selection and evidence generation. The panel participated in three structured plenary sessions. Additional external experts were engaged to provide complementary input in areas, such as tumor-specific characteristics and statistical methodology. Consensus statements were developed through an iterative process of discussion, critical appraisal, and refinement across and between sessions. RESULTS:The expert panel issued twelve recommendations to improve value assessment in oncology. These include tailoring clinical endpoints to treatment type, tumor characteristics, and stage; complementing overall survival with milestone analysis and quality-of-life measures; and standardizing real-world evidence collection across the healthcare system. The panel advocated for a national portfolio of prioritized endpoints, appropriate statistical methods by context, and the conditional use of early-phase data for decision-making. Additional recommendations addressed the use of synthetic control arms, flexible reimbursement models, advanced analytics (e.g., AI and Big Data), evaluator expertise, and the promotion of stakeholder training and transparency. CONCLUSIONS:Addressing the challenges of clinical endpoint selection and evidence generation is essential to reduce uncertainty in the value assessment of innovative oncology treatments. The twelve expert recommendations outlined in this study provide a structured roadmap to improve methodological consistency, enhance the relevance and robustness of clinical and real-world data, and promote a more adaptive and transparent evaluation framework. These proposals aim to support more evidence-based, equitable, and sustainable decision-making within the Spanish healthcare system, while aligning with broader European initiatives in oncology drug assessment.
BACKGROUND AND AIMS:Evidence regarding the influence of vedolizumab (VDZ) on extraintestinal manifestations (EIMs) of inflammatory bowel disease (IBD) is limited. Our aim was to analyze the effectiveness of VDZ in preexisting EIMs and the occurrence of de novo EIMs during VDZ therapy for IBD. METHODS:This observational, multicenter, retrospective cohort study included patients from the Spanish ENEIDA registry. All EIMs were assessed at baseline, and clinical response and worsening of IBD and EIMs were evaluated at 3 and 12 months after VDZ initiation, according to the physician's assessment. RESULTS:We retrospectively identified 551 patients with IBD treated with VDZ. At baseline, 133 patients (24.1%) had preexisting EIMs, with 77 having active EIMs. At 3 months, 29.9% of these patients showed clinical improvement, 16.9% experienced worsening, and 53.2% remained unchanged. Clinical response of IBD at 3 months was the only factor associated with EIM improvement (OR 3.72; 95% CI 1.08-12.83). Among 56 patients with inactive EIMs at baseline, 13.5% experienced worsening after 12 months. During follow-up, 25 patients (4.5%) developed 27 de novo EIMs. The presence of 2 preexisting EIMs was the only factor associated with de novo EIM onset (OR 16.2; 95% CI 4.3-60.9). Worsening of preexisting EIMs or de novo EIMs led to VDZ discontinuation in 15 patients (5.8% of all patients who discontinued VDZ and 2.7% of the entire cohort). CONCLUSIONS:VDZ achieved clinical response of active EIMs in nearly one-third of patients after 3 months. Although infrequent, VDZ may exacerbate inactive EIMs and induce de novo EIMs during therapy, potentially leading to treatment discontinuation.
BackgroundThe relationship between the neurodevelopment in infants exposed to maternal Type-1 diabetes and changes in fetal DNA methylation has not yet been investigated.AimThis hypothesis-generating study, we aimed to determine whether neurodevelopmental outcomes in offspring from mothers with Type-1 diabetes are associated with intrauterine epigenetic changes in fetal DNA.Material and MethodsWe conducted a prospective, pilot case-control study, comparing infants exposed to maternal Type-1-diabetes with control infants. Cord blood DNA samples were analyzed using the TruSeq-Methyl-Capture-EPIC-Kit, covering over 3.3 million CpGs. The Bayley-III Scales were used to assess infant neurodevelopment, and the scores were correlated with the newborn DNA methylation data.ResultsIn infants exposed to maternal diabetes, we identified 108 differentially methylated genes enriched in pathways crucial for neurodevelopment: Vocal, Imitative and Observational Learning, Synapse Organization, and Neurogenesis. The greatest methylation differences were observed in differentially methylated regions (DMRs) annotated to key neurological genes: MYT1L (21.61%, q=1.97E-07), NRXN1 (12.30%, q=5.04E-75), SHANK3 (11.62%, q=9.81E-06) and KIRREL3 (7.35%, q= 1.53E-23). Both, NRXN1 and SHANK3, were enriched across all identified neurodevelopmental pathways. At two years of age, the infants exposed to maternal Type-1 diabetes scored significantly lower on the Bayley-III Scales across the cognitive, language, and motor domains. Methylation values across loci annotated to ten neurodevelopment-associated genes were linked to Bayley-III cognitive, language, and/or motor domain scores—with MYT1L and NRXN1 showing significant correlation with the Bayley-III language domain score.ConclusionsWhile further confirmation is needed, we provide the first results supporting the hypothesis that neurodevelopmental alterations observed in offspring of mothers with Type-1 diabetes are potentially associated with DNA methylation changes during intrauterine life which can be identified at birth.
Abstract Objectives To analyze the interaction between type 1 diabetes mellitus (T1DM) and gender-affirming hormone therapy (GAHT), assessing its impact on glycemic control and on clinical decision-making related to GAHT, gender-affirming surgery, and therapeutic management of T1DM. Material and Methods Retrospective descriptive study of a case series of transgender individuals with T1DM followed in a specialized gender identity clinic. Five patients with longitudinal follow-up were included (four trans women and one trans man). Demographic and clinical variables, transition-related data, glycemic control parameters (HbA1c and basic continuous glucose monitoring metrics), and use of diabetes technology were collected. The temporal relationship between GAHT initiation, glycemic control, and clinical decision-making was analyzed using descriptive methods. Results Mean age was 28.4 years (range 19-41), with a mean age at T1DM diagnosis of 11.6 years. Four patients were receiving GAHT, initiated at a mean age of 19.8 years. Mean baseline HbA1c was 8.7%, increasing to 9.0% at 6 months and 8.9% at 12 months. T1DM did not influence the indication, initiation, or intensity of GAHT in any case. However, in two patients, gender-affirming surgery (vaginoplasty) was postponed due to the need for preoperative optimization of glycemic control. Only one patient was treated with continuous subcutaneous insulin infusion (CSII); this patient showed a clinically relevant improvement in glycemic control after pump initiation, with HbA1c decreasing from 8.2% to 6.1% at 6 months. In the remaining four cases, CSII was not initiated: in three patients due to poor treatment adherence and difficulties attending nursing follow-up (currently awaiting pump initiation), and in one patient due to adequate glycemic control without advanced technology. No systematic deterioration in glycemic control attributable to GAHT initiation was observed. Conclusions In this case series, T1DM did not represent a barrier to access to or intensity of GAHT. Glycemic control did influence the planning of gender-affirming surgery, requiring prior metabolic optimization in some cases. GAHT was not associated with a systematic worsening of glycemic control. The improvement observed in the single patient using insulin pump therapy suggests that access to diabetes technology, together with adequate adherence, may play a key role in metabolic control among transgender individuals with T1DM.
To develop and internally validate the PANTHEIA-SIRI prognostic model, which integrates log-transformed systemic inflammation response index (SIRI) with clinical predictors, to estimate overall survival (OS) in metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with first-line chemotherapy. We used data from the multicenter PANTHEIA-SEOM registry. OS was defined from chemotherapy start. The model was fitted as a Weibull accelerated failure time model in the survival-analysis population with multiple imputation. Predictors were log-transformed baseline SIRI, modeled with restricted cubic splines, ECOG, tumor burden, chemotherapy regimen, and anorexia-cachexia syndrome. Internal validation used a separate, non-overlapping cohort from the same registry; the centers contributing to each cohort are listed in a supplementary annex. TRIPOD was followed. Discrimination was assessed with Harrell´s C-index and calibration with IPCW Brier scores and IPA. The derivation cohort comprised 672 patients with SIRI data (593 analyzed for survival) across 22 Spanish hospitals (2015–2025); 80.1 https://pantheia-siri.shinyapps.io/calc/ ) may support prognostic communication, treatment-intensity selection, and supportive-care planning. Routine clinical implementation will require further validation in larger, fully independent cohorts.
